Journal Mobile Options
Table of Contents
Vol. 65, No. 1, 2012
Issue release date: December 2011
Section title: Original Paper
Free Access
Neuropsychobiology 2012;65:45–54

Perception of a Naturalistic Stressor Interacts with 5-HTTLPR/rs25531 Genotype and Gender to Impact Reward Responsiveness

Nikolova Y.a · Bogdan R.a · Pizzagalli D.A.a, b
aAffective Neuroscience Laboratory, Department of Psychology, Harvard University, Cambridge, Mass., and bCenter for Depression, Anxiety and Stress Research and Neuroimaging Center, McLean Hospital and Harvard Medical School, Belmont, Mass., USA
email Corresponding Author

Diego A. Pizzagalli

Center for Depression, Anxiety and Stress Research

Room 233C, McLean Hospital

115 Mill Street, Belmont, MA 02478 (USA)

Tel. +1 617 855 4230, E-Mail


  1. Brown GW HT: Social Origins of Depression: A Study of Psychiatric Disorder in Women. New York, Free Press, 1978.
  2. Kendler KS, Karkowski LM, Prescott CA: Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 1999;156:837–841.
  3. Paykel ES, Myers JK, Dienelt MN, Klerman GL, Lindenthal JJ, Pepper MP: Life events and depression: a controlled study. Arch Gen Psychiatry 1969;21:753–760.
  4. van Praag HM: Can stress cause depression? Prog Neuro-Psychoph 2004;28:891–907.
  5. Anisman H, Matheson K: Stress, depression, and anhedonia: caveats concerning animal models. Neurosci Biobehav Rev 2005;29:525–546.
  6. Willner P: Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 2005;52:90–110.
  7. Berenbaum H, Connelly J: The effect of stress on hedonic capacity. J Abnorm Psychol 1993;102:474–481.
  8. Bogdan R, Pizzagalli DA: Acute stress reduces reward responsiveness: Implications for depression. Biol Psychiatry 2006;60:1147–1154.
  9. Bogdan R, Perlis RH, Fagerness J, Pizzagalli DA: The impact of mineralocorticoid receptor iso/val genotype (rs5522) and stress on reward learning. Genes Brain Behav 2010;9:658–667.
  10. Pizzagalli DA, Jahn AL, O’Shea JP: Toward an objective characterization of an anhedonic phenotype: a signal-detection approach. Biol Psychiatry 2005;57:319–327.
  11. Pizzagalli DA, Bogdan R, Ratner KG, Jahn AL: Increased perceived stress is associated with blunted hedonic capacity: potential implications for depression research. Behav Res Ther 2007;45:2742–2753.
  12. Pruessner JC, Dedovic K, Khalili-Mahani N, Engert V, Pruessner M, Buss C, Renwick R, Dagher A, Meaney MJ, Lupien S: Deactivation of the limbic system during acute psychosocial stress: evidence from positron emission tomography and functional magnetic resonance imaging studies. Biol Psychiatry 2008;63:234–240.
  13. Lumley MN, Harkness, KL: Specificity in the relations among childhood adversity, early maladaptive schemas, and symptom profiles in adolescent depression. Cogn Ther Res 2007;31:639–657.

    External Resources

  14. Dillon DG, Holmes AJ, Birk JL, Brooks N, Lyons-Ruth K, Pizzagalli DA: Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood. Biol Psychiatry 2009;66:206–213.
  15. Bruijnzeel AW: Kappa-opioid receptor signaling and brain reward function. Brain Res Rev 2009;62:127–146.
  16. Bearer EL, Zhang X, Janvelyan D, Boulat B, Jacobs RE: Reward circuitry is perturbed in the absence of the serotonin transporter. NeuroImage 2009;46:1091–1104.
  17. Sanders AC, Hussain AJ, Hen R, Zhuang X: Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward. Neuropsychopharmacology 2007;32:2321–2329.
  18. Dremencov E, El Mansari M, Blier P: Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci 2009;34:223–229.
  19. Schultz W: Getting formal with dopamine and reward. Neuron 2002;36:241–263.
  20. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP: Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;66:2621–2624.
  21. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H: Influence of life stress on depression: moderation by a polymorphism in the 5-htt gene. Science 2003;301:386–389.
  22. Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR: Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 2009;301:2462–2471.
  23. Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA: An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 2005;29:8–16.
  24. Zalsman G, Huang YY, Oquendo MA, Burke AK, Hu XZ, Brent DA, Ellis SP, Goldman D, Mann JJ: Association of a triallelic serotonin transporter gene promoter region (5- HTTLPR) polymorphism with stressful life events and severity of depression. Am J Psychiatry 2006;163:1588–1593.
  25. Brummett BH, Boyle SH, Siegler IC, Kuhn CM, Ashley-Koch A, Jonassaint CR, Zuchner S, Collins A, Williams RB: Effects of environmental stress and gender on associations among symptoms of depression and the serotonin transporter gene linked polymorphic region (5-HTTLPR). Behav Genet 2008;38:34–43.
  26. Sjoberg RL, Nilsson KW, Nordquist N, Ohrvik J, Leppert J, Lindstrom L, Oreland L: Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol 2006;9:443–449.
  27. Dickerson SS, Kemeny ME: Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 2004;130:355–391.
  28. Chapman LJ, Chapman JP: The measurement of handedness. Brain Cogn 1987;6:175–183.
  29. Beck A, Steer RA, Brown GK: Beck Depression Inventory Manual, ed 2. San Antonio, The Psychological Corporation, 1996.
  30. Watson D, Weber K, Assenheimer JS, Clark LA, Strauss ME, Mccormick RA: Testing a tripartite model. I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J Abnorm Psychol 1995;104:3–14.
  31. Cohen S, Kamarck T, Mermelstein R: A global measure of perceived stress. J Health Soc Behav 1983;24:385–396.
  32. Gard DE, Gard MG, Kring AM, John OP: Anticipatory and consummatory components of the experience of pleasure: a scale development study. J Res Pers 2006;40:1086–1102.

    External Resources

  33. Tripp G, Alsop B: Sensitivity to reward frequency in boys with attention deficit hyperactivity disorder. J Clin Child Psychol 1999;28:366–375.
  34. Pizzagalli DA, Iosifescu D, Hallett LA, Ratner KG, Fava M: Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. J Psychiatr Res 2009;43:76–87.

    External Resources

  35. Liu WH, Chan RC, Wang LZ, Huang J, Cheung EF, Gong QY, Gollan JK: Deficits in sustaining reward responses in subsyndromal and syndromal major depression. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:1045–1052.
  36. Bogdan R, Pizzagalli DA: The heritability of hedonic capacity and perceived stress: a twin study evaluation of candidate depressive phenotypes. Psychol Med 2009;39:211–218.
  37. Moss S, Prosser H, Costello H, Simpson N, Patel P, Rowe S, Turner S, Hatton C: Reliability and validity of the pas-add checklist for detecting psychiatric disorders in adults with intellectual disability. J Intellect Disabil Res 1998;42:173–183.
  38. Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL: Simultaneous genotyping of four functional loci of human slc6a4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry 2006;11:224–226.
  39. Kendler KS, Kuhn J, Prescott CA: The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression. Am J Psychiatry 2004;161:631–636.
  40. Mandelli L, Serretti A, Marino E, Pirovano A, Calati R, Colombo C: Interaction between serotonin transporter gene, catechol-o-methyltransferase gene and stressful life events in mood disorders. Int J Neuropsychopharmacol 2007;10:437–447.
  41. Pizzagalli DA, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R, Dougherty DD, Iosifescu DV, Rauch SL, Fava M: Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry 2009;166:702–710.
  42. Johnson EO, Kamilaris TC, Chrousos GP, Gold PW: Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis. Neurosci Biobehav Rev 1992;16:115–130.
  43. Cabib S, Puglisi-Allegra S: Stress, depression and the mesolimbic dopamine system. Psychopharmacology (Berl) 1996;128:331–342.
  44. Mangiavacchi S, Masi F, Scheggi S, Leggio B, De Montis MG, Gambarana C: Long-term behavioral and neurochemical effects of chronic stress exposure in rats. J Neurochem 2001;79:1113–1121.
  45. Kohen R, Cain KC, Mitchell PH, Becker K, Buzaitis A, Millard SP, Navaja GP, Teri L, Tirschwell D, Veith R: Association of serotonin transporter gene polymorphisms with poststroke depression. Arch Gen Psychiatry 2008;65:1296–1302.
  46. Stein MB, Campbell-Sills L, Gelernter J: Genetic variation in 5HTTLPR is associated with emotional resilience. Am J Med Genet B Neuropsychiatr Genet 2009;150B:900–906.
  47. Charney DS: Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry 2004;161:195–216.
  48. Feder A, Nestler EJ, Charney DS: Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 2009;10:446–457.
  49. Fox E, Ridgewell A, Ashwin C: Looking on the bright side: biased attention and the human serotonin transporter gene. Proc Biol Sci 2009;276:1747–1751.
  50. Perez-Edgar K, Bar-Haim Y, McDermott JM, Gorodetsky E, Hodgkinson CA, Goldman D, Ernst M, Pine DS, Fox NA: Variations in the serotonin-transporter gene are associated with attention bias patterns to positive and negative emotion faces. Biol Psychol 2010;83:269–271.
  51. Watson KK, Ghodasra JH, Platt ML: Serotonin transporter genotype modulates social reward and punishment in rhesus macaques. PLoS One 2009;4:e4156.
  52. Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O: Involvement of cb1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl) 2002;159:379–387.
  53. Nielsen CK, Arnt J, Sanchez C: Intracranial self-stimulation and sucrose intake differ as hedonic measures following chronic mild stress: interstrain and interindividual differences. Behav Brain Res 2000;107:21–33.
  54. Grabe HJ, Lange M, Wolff B, Volzke H, Lucht M, Freyberger HJ, John U, Cascorbi I: Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden. Mol Psychiatry 2005;10:220–224.
  55. Stroud LR, Salovey P, Epel ES: Sex differences in stress responses: Social rejection versus achievement stress. Biol Psychiatry 2002;3223
  56. Spreckelmeyer KN, Krach S, Kohls G, Rademacher L, Irmak A, Konrad K, Kircher T, Grunder G: Anticipation of monetary and social reward differently activates mesolimbic brain structures in men and women. Soc Cogn Affect Neurosci 2009;4:158–165.
  57. Stotland E: The Psychology of Hope. San Francisco, Jossey Bass, 1969.
  58. Hammen C: Stress and depression. Annu Rev Clin Psychol 2005;1:293–319.
  59. Morris BH, Rottenberg J: Does stress reduce hedonic capacity in anxiety? Poster presented at the 23rd Annual Meeting of the Society for Research in Psychopathology, Minneapolis, 2009.
  60. Arai K, Nakagomi Y, Iketani M, Shimura Y, Amemiya S, Ohyama K, Shibasaki T: Functional polymorphisms in the mineralocorticoid receptor and amirolide-sensitive sodium channel genes in a patient with sporadic pseudohypoaldosteronism. Hum Genet 2003;112:91–97.
  61. DeRijk RH, Wust S, Meijer OC, Zennaro MC, Federenko IS, Hellhammer DH, Giacchetti G, Vreugdenhil E, Zitman FG, de Kloet ER: A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. J Clin Endocrinol Metab 2006;91:5083–5089.
  62. Kuningas M, de Rijk RH, Westendorp RG, Jolles J, Slagboom PE, van Heemst D: Mental performance in old age dependent on cortisol and genetic variance in the mineralocorticoid and glucocorticoid receptors. Neuropsychopharmacology 2007;32:1295–1301.